Monomeric compositions effective as wound closure devices

ABSTRACT

A biocompatible monomer composition includes: (A) at least one monomer, which forms a medically acceptable polymer; (B) at least one plasticizing agent present in the composition in an amount of from 0.5 wt. % to 15 wt. % of the composition; and (C) at least one acidic stabilizing agent having a pK a  ionization constant of from about 1 to about 7. The composition can be applied to a variety of materials and is particularly suitable as in vivo tissue adhesive. A method of joining together in vivo two surfaces, e.g., body tissues, includes (a) holding damaged tissue edges together to form abutted tissue surfaces; (b) applying to the abutted tissue surfaces an excessive amount of a composition containing 1) at least one monomer, which forms a medically acceptable biodegradable polymer, 2) at least one plasticizing agent; and 3) at least one acidic stabilizing agent; and (c) maintaining the surfaces in contact until the composition polymerizes to form a thick film of polymerized composition bridging the abutted tissue surfaces.

This is a Division of application Ser. No. 08/609,921 filed Feb. 29,1996, which is now U.S. Pat. No. 5,981,621.

FIELD OF THE INVENTION

This invention relates to monomer and polymer compositions useful toform biomedical adhesives and sealants, and methods of applying them.More particularly, this invention relates to wound closure monomer andpolymer compositions and their use for medical, surgical and other invivo applications.

BACKGROUND

Products in primary use for wound closure are surgical sutures andstaples. Sutures are recognized to provide adequate wound support.However, sutures cause additional trauma to the wound site (by reason ofthe need for the needle and suture to pass through tissue and the needto anesthetize the wound area via needle application) and aretime-consuming to place, and, at skin level, can cause unattractivewound closure marks. Surgical staples have been developed to speed woundapposition and provide improved cosmetic results. However, surgicalstaples also impose additional wound trauma and require the use ofancillary and often expensive devices for positioning and applying thestaples. Both sutures and staples are especially problematic inpediatric cases where the patient may have a strong fear response andrefuse to cooperate with their placement, and in geriatric cases wherethe skin tissue is weaker and prone to tearing.

Alternatively, adhesives have been proposed as wound closure devices.One group of such adhesives is the monomeric forms ofalpha-cyanoacrylates.

Reference is made, for example, to U.S. Pat. Nos. 5,328,687 to Leung etal; U.S. Pat. No. 3,527,841 to Wicker et al.; U.S. Pat. No. 3,722,599 toRobertson et al.; U.S. Pat. No. 3,995,641 to Kronenthal et al.; and U.S.Pat. No. 3,940,362 to Overhults, which disclose alpha-cyanoacrylatesthat are useful as surgical adhesives. All of the foregoing referencesare hereby incorporated by reference herein.

Typically, the cyanoacrylate surgical adhesive is applied to one or bothsurfaces of wounds or incisions, including the internal portions of thewound, with any excess adhesive being quickly removed from the bondingsurfaces. Subsequently, the edges of the wound are held together untilthey adhere. See U.S. Pat. No. 3,559,652 to Coover, Jr. et al. Twocoatings of adhesive may be applied to the wound surfaces. However, thismethod of application produces significant levels of histoxicity due tothe surgical adhesive being trapped within the wound site.

An additional method of application of the cyanoacrylate surgicaladhesive to wounds or incisions involves the formation of a bridge overthe wound site. As described in U.S. Pat. No. 3,667,472 to Halpern, theincised tissues are held together and maintained in fixed relationshipuntil a cyanoacrylate adhesive has been applied over the incision andallowed the necessary time to develop a bond. Excess adhesive is removedfrom the incision. However, the composition utilized in this processsuffers from inadequate film strength and flexibility with highhistotoxicity in wound sites.

These conventional methods of application of tissue adhesive generallydo not specify a particular method that is preferable, nor is there anymention of placing more than minimal amounts of glue upon wounds. Theconventional application techniques strive to reduce application ofexcessive amounts of tissue adhesive to the wound due to histoxicity.

A topical tissue adhesive commercially available is Histoacryl®available from B. Braun Melsungen AG of Germany. The manufacturerrecommends use of this adhesive only for closure of minor skin woundsand not for internal use. Moreover the manufacturer recommends that theadhesive be used sparingly or in thin films because thick films do notincrease the film strength and can lead to necrosis of surroundingtissue due to thermogenic reaction. Moreover, films formed from thisadhesive are brittle, permitting severe dehiscence of wounds.

Plasticizers have been added to cyanoacrylate surgical adhesivecompositions. See, for example, U.S. Pat. Nos. 3,759,264 to Coover, Jr.et al., U.S. Pat. No. 3,667,472 to Halpern, U.S. Pat. No. 3,559,652 toBanitt, the subject matter of which is incorporated herein by reference.However, the incorporation of plasticizers in such compositions has ledto decreased film strength of the polymerized material. Accordingly,such compositions have been utilized only within the wound site and notover the wound site as a bridge.

Other additives have been employed in cyanoacrylate surgical adhesivesfor the purposes of modifying the cure rate and shelf life of theadhesives. For example, cyanoacrylate polymerization inhibitors orstabilizers including Lewis acids, such as sulfur dioxide, nitric oxide,boron trifluoride and other acidic substances, including hydroquinonemonomethyl ether, hydroquinone, nitrohydroquinone, catechol andhydroquinone monoethyl ether. See, for example, U.S. Pat. No. 3,559,652to Banitt, the subject matter of which is incorporated herein byreference. These compositions contain significant amounts of impuritiesand, thus, require substantial amounts of stabilizer to inhibitpremature polymerization of the monomer.

Other adhesives include both plasticizers and stabilizing agents. Forexample, U.S. Pat. No. 5,480,935 to Greff et al. describes a tissueadhesive having a plasticizer and a polymerization inhibitor. However,the plasticizers disclosed therein (i.e., alkyl phthalates) are highlytoxic and are not suitable for use in biocompatible medical adhesives.

SUMMARY OF THE INVENTION

The present invention is based on the discovery that combining themonomers described hereinafter with a plasticizing agent and an acidicstabilizing agent provides a surgical adhesive composition that, afterapplication to wounds or incisions, polymerizes to form a strong andflexible bond on the wound or incision site. Furthermore, the presentinvention provides a process for application of this surgical adhesivecomposition in a bridge structure that provides an unexpectedly improvedbond strength over conventional application techniques of thepolymerized composition on the wound or incision site, which increasesthe effectiveness of such monomers and polymers in in vivo applications.

The surgical adhesive forms a flexible and strong bond over wounds andincisions. Moreover, the method of applying a surgical adhesive to awound or incision provides a strong and flexible biocompatible bond.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

One embodiment of the present invention provides a wound closure monomercomposition, comprising:

A) at least one monomer, which forms a medically acceptable woundclosure polymer:

B) at least one plasticizing agent; and

C) at least one acidic stabilizing agent.

In other embodiments, the present invention is directed to methods ofusing the above-described monomers, copolymers and polymers madetherefrom for biomedical purposes.

In one such embodiment, the edges of a wound or incision are heldtogether and an excessive amount of the above-described surgicaladhesive composition is applied to the already pinched or abuttedopposing wound edges, preferably utilizing more than one applicationstroke. This process forms a bridge over the abutted opposing woundedges that is flexible and possesses high tensile strength. Theexcessive amount of adhesive placed on the abutted opposing wound edgesforms a thick film thereon and unexpectedly increases film strength.

For example, the present invention includes a method of forming abiocompatible film across abutted tissue surfaces, comprising; (a)holding together at least two tissue surfaces to form abutted tissuesurfaces, (b) applying across said abutted tissue surfaces an adhesivebiocompatible monomer composition, and (c) allowing said composition topolymerize and form a biocompatible film on said abutted tissue surfaceshaving an in vivo film strength of at least 70 mmHg of vacuum pressurerequired to induce wound failure, generally from 70 mmHg to 400 mmHg ofvacuum pressure required to induce wound failure, preferably from 90mmHg to 400 mmHg of vacuum pressure required to induce wound failure,and more preferably from 100 mmHg to 400 mmHg of pressure required toinduce wound failure.

Preferably, the monomer is an alpha-cyanoacrylate. The monomercompositions of this invention and polymers formed therefrom are usefulas tissue adhesives, sealants for preventing bleeding or for coveringopen wounds, and in other biomedical applications. They find uses in,for example, apposing surgically incised or traumatically laceratedtissues; setting fractured bone structures; retarding blood flow fromwounds; and aiding repair and regrowth of living tissue.

As above-mentioned, conventional surgical adhesive compositions haveincluded plasticizers with the adverse effect of reducing the filmstrength. It has been discovered that, contrary to prior belief, thefilm strength (e.g., toughness) under certain conditions is notadversely reduced upon the addition of greater amounts of plasticizingagent. Depending on the particular acidic stabilizing agent and thepurity of the monomer utilized in the adhesive composition, the additionof greater amounts of plasticizing agent may increase the toughness ofthe resulting bond formed on the wound. It has been discovered that weakacidic stabilizing agents do not significantly affect the polymerizationof the monomer in the present composition and provide increased filmstrength with increasing amounts of plasticizing agents.

Monomers that may be used in this invention are polymerizable, e.g.anionically polymerizable or free radical polymerizable, to formpolymers. Such monomers include those that form polymers, which may, butdo not need to, biodegrade. Reference is made, for example, to U.S. Pat.No. 5,328,687, which is hereby incorporated by reference herein. Asdefined herein, “histotoxicity” refers to adverse tissue response, suchas inflammation due to the presence of toxic materials in the tissue.

Useful 1,1-disubstituted ethylene monomers include, but are not limitedto, monomers of the formula:

CHR═CXY  (I)

wherein X and Y are each strong electron withdrawing groups, and R is H,—CH═CH₂ or, provided that X and Y are both cyano groups, a C₁-C₄ alkylgroup.

Examples of monomers within the scope of formula (I) includealpha-cyanoacrylates, vinylidene cyanides, C₁-C₄ alkyl homologues ofvinylidene cyanides, dialkyl methylene malonates, acylacrylonitriles,vinyl sulfinates and vinyl sulfonates of the formula CH₂═CX′Y′wherein X′is —SO₂R′ or —SO₃R′ and Y′ is —CN, —COOR′, —COCH₃, —SO₂R′ or —SO₃R′, andR′ is H or hydrocarbyl.

Preferred monomers of formula (I) for use in this invention arealpha-cyanoacrylates. These monomers are known in the art and have theformula

wherein R² is hydrogen and R³ is a hydrocarbyl or substitutedhydrocarbyl group; a group having the formula —R⁴—O—R⁵—O—R⁶, wherein R⁴is a 1,2-alkylene group having 2-4 carbon atoms, R⁵ is an alkylene grouphaving 2-4 carbon atoms, and R⁶ is an alkyl group having 1-6 carbonatoms; or a group having the formula

wherein R⁷ is

or —C(CH₃)₂— and R⁸ is an organic radical.

Examples of suitable hydrocarbyl and substituted hydrocarbyl groupsinclude straight chain or branched chain alkyl groups having 1-16 carbonatoms; straight chain or branched chain C₁-C₁₆ alkyl groups substitutedwith an acyloxy group, a haloalkyl group, an alkoxy group, a halogenatom, a cyano group, or a haloalkyl group; straight chain or branchedchain alkenyl groups having 2 to 16 carbon atoms; straight chain orbranched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkylgroups; aralkyl groups; alkylaryl groups; and aryl groups.

The organic radical R⁸ may be substituted or unsubstituted and may bestraight chain, branched or cyclic, saturated, unsaturated or aromatic.Examples of such organic radicals include C₁-C₈ alkyl radicals, C₂-C₈alkenyl radicals, C₂-C₈ alkynyl radicals, C₃-C₁₂ cycloaliphaticradicals, aryl radicals such as phenyl and substituted phenyl andaralkyl radicals such as benzyl, methylbenzyl and phenylethyl. Otherorganic radicals include substituted hydrocarbon radicals, such ashalo(e.g., chloro-, fluoro- and bromo-substituted hydrocarbons) andoxy-(e.g., alkoxy substituted hydrocarbons) substituted hydrocarbonradicals. Preferred organic radicals are alkyl, alkenyl and alkynylradicals having from 1 to about 8 carbon atoms, and halo-substitutedderivatives thereof. Particularly preferred are alkyl radicals of 4 to 6carbon atoms.

In the cyanoacrylate monomer of formula (II), R³ is preferably an alkylgroup having 1-10 carbon atoms or a group having the formula —AOR⁹,wherein A is a divalent straight or branched chain alkylene oroxyalkylene radical having 2-8 carbon atoms, and R⁹ is a straight orbranched alkyl radical having 1-8 carbon atoms.

Examples of groups represented by the formula —AOR⁹ include1-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl,and 2-ethoxy ethyl.

The preferred alpha-cyanoacrylate monomers used in this invention are2-octyl cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexylcyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutylcyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxyethylcyanoacrylate, or 1-methoxy-2-propyl cyanoacrylate.

The alpha-cyanoacrylates of formula (II) can be prepared according tomethods known in the art. Reference is made, for example, to U.S. Pat.Nos. 2,721,858 and 3,254,111, each of which is hereby incorporated byreference herein. For example, the alpha cyanoacrylates can be preparedby reacting an alkyl cyanoacetate with formaldehyde in a non-aqueousorganic solvent and in the presence of a basic catalyst, followed bypyrolysis of the anhydrous intermediate polymer in the presence of apolymerization inhibitor. The alpha-cyanoacrylate monomers prepared withlow moisture content and essentially free of impurities are preferredfor biomedical use.

The alpha-cyanoacrylates of formula (II) wherein R³ is a group havingthe formula —R⁴—O—R⁵—O—R⁶ can be prepared according to the methoddisclosed in U.S. Pat. No. 4,364,876 to Kimura et al., which is herebyincorporated by reference herein. In the Kimura et al. method, thealpha-cyanoacrylates are prepared by producing a cyanoacetate byesterifying cyanoacetic acid with an alcohol or by transesterifying analkyl cyanoacetate and an alcohol; condensing the cyanoacetate andformaldehyde or para-formaldehyde in the presence of a catalyst at amolar ratio of 0.5-1.5:1, preferably 0.8-1.2:1, to obtain a condensate;depolymerizing the condensation reaction mixture either directly orafter removal of the condensation catalyst to yield crude cyanoacrylate;and distilling the crude cyanoacrylate to form a high puritycyanoacrylate.

The alpha-cyanoacrylates of formula (II) wherein R³ is a group havingthe formula

can be prepared according to the procedure described in U.S. Pat. No.3,995,641 to Kronenthal et al., which is hereby incorporated byreference herein. In the Kronenthal et al. method, suchalpha-cyanoacrylate monomers are prepared by reacting an alkyl ester ofan alpha-cyanoacrylic acid with a cyclic 1,3-diene to form a Diels-Alderadduct which is then subjected to alkaline hydrolysis followed byacidification to form the corresponding alpha-cyanoacrylic acid adduct.The alpha-cyanoacrylic acid adduct is preferably esterified by an alkylbromoacetate to yield the corresponding carbalkoxymethylalpha-cyanoacrylate adduct. Alternatively, the alpha-cyanoacrylic acidadduct may be converted to the alpha-cyanoacrylyl halide adduct byreaction with thionyl chloride. The alpha-cyanoacrylyl halide adduct isthen reacted with an alkyl hydroxyacetate or a methyl substituted alkylhydroxyacetate to yield the corresponding carbalkoxymethylalpha-cyanoacrylate adduct or carbalkoxy alkyl alpha-cyanoacrylateadduct, respectively. The cyclic 1,3-diene blocking group is finallyremoved and the carbalkoxy methyl alpha-cyanoacrylate adduct or thecarbalkoxy alkyl alpha-cyanoacrylate adduct is converted into thecorresponding carbalkoxy alkyl alpha-cyanoacrylate by heating the adductin the presence of a slight deficit of maleic anhydride.

Examples of monomers of formula (II) include cyanopentadienoates andalpha-cyanoacrylates of the formula:

wherein Z is —CH═CH₂ and R³ is as defined above. The monomers of formula(III) wherein R³ is an alkyl group of 1-10 carbon atoms, i.e., the2-cyanopenta-2,4-dienoic acid esters, can be prepared by reacting anappropriate 2-cyanoacetate with acrolein in the presence of a catalystsuch as zinc chloride. This method of preparing 2-cyanopenta-2,4-dienoicacid esters is disclosed, for example, in U.S. Pat. No. 3,554,990, whichis hereby incorporated by reference herein.

Preferred monomers are alkyl alpha-cyanoacrylates and more preferablyoctyl alpha-cyanoacrylates, especially 2-octyl alpha-cyanoacrylate.Monomers utilized in the present application should be very pure andcontain few impurities (e.g., surgical grade).

Component B) of the compositions of this invention is at least oneplasticizing agent that imparts flexibility to the polymerized monomerformed on the wound or incision. The plasticizing agent preferablycontains little or no moisture and should not significantly affect thepolymerization of the monomer.

Examples of suitable plasticizers include acetyl tributyl citrate,dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate,tri(p-cresyl) phosphate, glyceryl triacetate, glyceryl tributyrate,diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate,lauric acid, trioctyl trimellitate, dioctyl glutarate and mixturesthereof. Preferred plasticizers are tributyl citrate and acetyl tributylcitrate.

Component C) of the compositions of this invention is at least oneacidic stabilizing agent that inhibits polymerization. Such stabilizingagents may also include mixtures of anionic stabilizing agents andradical stabilizing agents.

Examples of suitable anionic stabilizing agents include sulfur dioxide,sulfonic acid, lactone, boron trifluoride, organic acids, alkyl sulfate,alkyl sulfite, 3-sulfolene, alkylsulfone, alkyl sulfoxide, mercaptan,and alkyl sulfide and mixtures thereof. Preferable anionic stabilizingagents are acidic stabilizing agents of organic acids such as aceticacid or phosphoric acid with acetic acid being a more preferable acidicstabilizing agent. The maximum amount of sulfur dioxide present in theadhesive composition should be less than 50 ppm, and preferably lessthan 30 ppm.

Examples of suitable radical stabilizing agents include hydroquinone,hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone,2-hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, butylatedhydroxy anisole, butylated hydroxy toluene, and t-butyl hydroquinone.

Suitable acidic stabilizing agents include those having pK_(a)ionization constants ranging from about 0 to about 7, preferably fromabout 1 to about 6, and more preferably from about 2 to about 5.5. Forexample, suitable acidic stabilizing agents include: hydrogen sulfide(pK_(a) 7.0), carbonic acid (pK_(a) 6.4), triacetylmethane (pK_(a) 5.9),acetic acid (pK_(a) 4.8), benzoic acid (pK_(a) 4.2), 2,4-dinitrophenol(pK_(a) 4.0), formic acid (pK_(a) 3.7), nitrous acid (pK_(a) 3.3),hydrofluoric acid (pK_(a) 3.2), chloroacetic acid (pK_(a) 2.9),phosphoric acid (pK_(a) 2.2), dichloroacetic acid (pK_(a) 1.3),trichloroacetic acid (pK_(a) 0.7), 2,4,6-trinitrophenol (picric acid)(pK_(a) 0.3), trifluoroacetic acid (pK_(a) 0.2), and mixtures thereof.

When adding the above-mentioned weak acidic stabilizing agents to theadhesive composition, it has been discovered that the addition ofplasticizing agents in amounts ranging from about 0.5 wt. % to about 16wt. %, preferably from about 3 wt. % to about 9 wt. %, and morepreferably from about 5 wt. % to about 7 wt % provides increased filmstrength (e.g., toughness) of the polymerized monomer over polymerizedmonomers having amounts of plasticizing agents and acidic stabilizingagents outside of the above ranges.

The concentration of the acidic stabilizing agents utilized may varydepending on the strength of the acid. For example, when using aceticacid, a concentration of 80-200 ppm (wt/wt), preferably 90-180 ppm(wt/wt), and more preferably 100-150 ppm (wt/wt) may be utilized. Whenusing a stronger acid, such as phosphoric acid a concentration range of20-80 ppm (wt/wt), preferably, 30-70 ppm (wt/wt) and more preferably40-60 ppm (wt/wt) may be utilized.

The compositions of this invention may also include at least onebiocompatible agent effective to reduce active formaldehydeconcentration levels produced during in vivo biodegradation of thepolymer (also referred to herein as “formaldehyde concentration reducingagents”). Preferably, this component is a formaldehyde scavengercompound. Examples of formaldehyde scavenger compounds useful in thisinvention include sulfites; bisulfites; mixtures of sulfites andbisulfites; ammonium sulfite salts; amines; amides; imides; nitriles;carbamates; alcohols; mercaptans; proteins; mixtures of amines, amides,and proteins; active methylene compounds such as cyclic ketones andcompounds having a β-dicarbonyl group; and heterocyclic ring compoundsfree of a carbonyl group and containing an NH group, with the ring madeup of nitrogen or carbon atoms, the ring being unsaturated or, whenfused to a phenyl group, being unsaturated or saturated, and the NHgroup being bonded to a carbon or a nitrogen atom, which atom isdirectly bonded by a double bond to another carbon or nitrogen atom.

Bisulfites and sulfites useful as the formaldehyde scavenger compound inthis invention include alkali metal salts such as lithium, sodium andpotassium salts, and ammonium salts, for example, sodium bisulfite,potassium, bisulfite, lithium bisulfite, ammonium bisulfite, sodiumsulfite, potassium sulfite, lithium sulfite, ammonium sulfite, and thelike.

Examples of amines useful in this invention include the aliphatic andaromatic amines such as, for example, aniline, benzidine,aminopyrimidine, toluene-diamine, triethylenediamine, diphenylamine,diaminodiphenylamine, hydrazines and hydrazide.

Suitable proteins include collagen, gelatin, casein, soybean protein,vegetable protein, keratin and glue. The preferred protein for use inthis invention is casein.

Suitable amides for use in this invention include urea, cyanamide,acrylamide, benzamide, and acetamide. Urea is the preferred amide.

Suitable alcohols include phenols, 1,4-butanediol, d-sorbitol, andpolyvinyl alcohol.

Examples of suitable compounds having a β-dicarbonyl group includemalonic acid, acetylacetone, ethylacetone, acetate, malonamide,diethylmalonate or another malonic. ester.

Preferred cyclic ketones for use in this invention include cyclohexanoneor cyclopentanone.

Examples of suitable heterocyclic compounds for use as the formaldehydescavenger in this invention are disclosed, for example, in U.S. Pat. No.4,127,382 (Perry) which is hereby incorporated by reference herein. Suchheterocyclic compounds include, for example, benzimidazole, 5-methylbenzimidazole, 2-methylbenzimidazole, indole, pyrrole, 1,2,4-triazole,indoline, benzotriazole, indoline, and the like.

A preferred formaldehyde scavenger for use in this invention is sodiumbisulfite.

In practicing this invention, the formaldehyde concentration reducingagent, e.g., formaldehyde scavenger compound, is added in an effectiveamount to the cyanoacrylate. The “effective amount” is that amountsufficient to reduce the amount of formaldehyde generated duringsubsequent in vivo biodegradation of the polymerized cyanoacrylate. Thisamount will depend on the type of active formaldehyde concentrationreducing agent, and can be readily determined without undueexperimentation by those skilled in the art.

The formaldehyde concentration reducing agent may be used in thisinvention in either free form or in microencapsulated form.

When microencapsulated, the formaldehyde concentration reducing agent isreleased from the microcapsule continuously over a period of time duringthe in vivo biodegradation of the cyanoacrylate polymer.

For purposes of this invention, the microencapsulated form of theformaldehyde concentration reducing agent is preferred because thisembodiment prevents or substantially reduces polymerization of thecyanoacrylate monomer by the formaldehyde concentration reducing agent,which increases shelf-life and facilitates handling of the monomercomposition during use.

Microencapsulation of the formaldehyde scavenger can be achieved, bymany known microencapsulation techniques. For example,microencapsulation can be carried out by dissolving a coating polymer ina volatile solvent, e.g., methylene chloride, to a polymer concentrationof about 6% by weight; adding a formaldehyde scavenger compound inparticulate form to the coating polymer/solvent solution under agitationto yield a scavenger concentration of 18% by weight; slowly adding asurfactant-containing mineral oil solution to the polymer solution underrapid agitation; allowing the volatile solvent to evaporate underagitation; removing the agitator; separating the solids from the mineraloil; and washing and drying the microparticles. The size of themicroparticles will range from about 0.001 to about 1000 microns.

The coating polymer for microencapsulating the formaldehydeconcentration reducing agent should be polymers which undergo in vivobioerosion, preferably at rates similar to or greater than thecyanoacrylate polymer formed by the monomer, and should have lowinherent moisture content. Such “bioerosion” can occur as a result ofthe physical or chemical breakdown of the encapsulating material, forexample, by the encapsulating material passing from solid to solute inthe presence of body fluids, or by biodegradation of the encapsulatingmaterial by agents present in the body.

Examples of coating materials which can be used to microencapsulate theformaldehyde concentration reducing agent include polyesters, such aspolyglycolic acid, polylactic acid, copolymers of polyglycolic acid andpolylactic acid, polycaprolactone, poly-β-hydroxybutyrate, copolymers ofepsilon-caprolactone and delta-valerolactone, copolymers ofepsilon-caprolactone and DL-dilactide, and polyester hydrogels;polyvinylpyrrolidone; polyamides; gelatin; albumin; proteins; collagen;poly(orthoesters); poly(anhydrides); poly(alkyl-2-cyanoacrylates);poly(dihydropyrans); poly(acetals); poly(phosphazenes); poly(urethanes);poly(dioxinones); cellulose; and starches.

Examples of the surfactant which can be added to the mineral oil includethose commercially available under the designations Triton x-100, Tween20 and Tween 80.

The composition of this invention may further contain one or moreadjuvant substances, such as thickening agents, medicaments, or thelike, to improve the medical utility of the monomer for particularmedical applications.

Suitable thickeners include, for example, poly-cyanoacrylates,polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers,polycaprolactone, lactic acid-caprolactone copolymers,poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates,copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates,and copolymers of alkyl methacrylates and butadiene.

To improve the cohesive strength of adhesives formed from thecompositions of this invention, difunctional monomeric cross-linkingagents may be added to the monomer compositions of this invention. Suchcrosslinking agents are known. Reference is made, for example, to U.S.Pat. No. 3,940,362 to Overhults, which is hereby incorporated byreference herein. Examples of suitable crosslinking agents include alkylbis(2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates,alkylene dimethacrylates, trimethylol propane triacrylate, and alkylbis(2-cyanoacrylates). A catalytic amount of an amine activated freeradical initiator is added to initiate polymerization of thecyanoacrylate monomer/crosslinking agent blend.

The compositions of this invention may further contain fibrousreinforcement and colorants, i.e., dyes and pigments. Examples ofsuitable fibrous reinforcement include PGA microfibrils, collagenmicrofibrils, cellulosic microfibrils, and olefinic microfibrils.Examples of suitable colorants include1-hydroxy-4-[4-methylphenylamino]-9,10 anthracenedione (D+C violet No.2); disodium salt of6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+CYellow No. 6);9-(o-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one,disodium salt, monohydrate (FD+C Red No. 3);2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-indole-5-sulfonicacid disodium salt (FD+C Blue No. 2); and [phtha-1-ocyaninato(2-)]copper.

The compositions of this invention can be used to join together twosurfaces by applying the present composition to the surface of opposingwound surfaces that are held together. Depending on the particularrequirements of the user, the adhesive compositions of this inventioncan be applied by known means such as with a glass stirring rod, sterilebrush or medicine dropper. However, in many situations a pressurizedaerosol dispensing package is preferred in which the adhesivecomposition is in solution with a compatible anhydrous propellant.

In one embodiment, the present invention is directed to a method ofjoining together in vivo two surfaces which comprises (a) holdingtogether tissue surfaces of a wound or incision to form an abuttedtissue surface; (b) applying to said abutted tissue surface acomposition of the present invention, e.g., a composition comprising 1)at least one monomer (e.g., a monomer of formula (I)) which forms amedically acceptable polymer, 2) a plasticizing agent and 3) a suitableacidic stabilizing agent; and (b) maintaining the surfaces in contactuntil said composition polymerizes.

As above-mentioned, conventional surgical adhesive compositions havebeen applied in very small quantities to wound surfaces before they areabutted, with care taken to remove excess adhesive. Thick films formedon wound surfaces have, in the past, resulted in increased histotoxicityof the wound tissues and increased film brittleness with no increasedfilm strength.

However, the present invention is directed to a method of joiningtogether in vivo two tissue surfaces by applying to an already abuttedtissue surface of a wound or incision a composition of this invention,preferably in more than one application or coating on the abutted tissuesurfaces to provide an excess of the adhesive composition on the abuttedtissue surfaces. Any excess adhesive applied directly on the abuttedtissue surface or on the immediate vicinity of the wound or incision ispreferably not removed, although excess applied to surrounding tissuenot proximate to the wound region may be removed.

A subsequent coating may be applied immediately after application of aprevious coating or after a previous coating has been completelypolymerized. Preferably, the monomer composition applied to the abuttedtissue surface is allowed to at least partially polymerize prior tosubsequent coatings or applications of additional monomer composition. Acoating of an adhesive composition of the present invention having amonomer different from the monomer of the first or previous coating maybe applied as the second or subsequent coating. Due to the addition ofthe plasticizing agent and the acidic stabilizing agent, the polymerformed on the abutted tissue surface possesses sufficient bond strengthand flexibility even with significant film or coating thicknesses.Suitable film thickness range from 0.1 mm to 2.0 mm or 3.0 mm or higher,preferably from 0.2 mm to 1.5 mm and more preferably from 0.4 mm to 0.8mm.

In another embodiment, the present invention is directed to a method ofjoining together in vivo two tissue surfaces by application of thepresent adhesive composition utilizing various applicators. Suchapplicators include crushable swab applicators, syringes and vials withvarious dispensing nozzles or tips.

For example, the applicator tip may be detachable from the applicatorcontainer holding the polymerizable and/or cross-linkable material. Suchan applicator tip could be attached to the applicator container prior touse and detached from the applicator container subsequent to use inorder to prevent premature polymerization or cross-linking of theunapplied material in the applicator container. At this point theapplicator tip may be discarded and a new applicator tip may be attachedto the applicator container for subsequent use or the applicator tip maybe reused.

Additionally, the applicator tip according to the present invention maycomprise multiple parts, with at least one part comprising theinitiator. For example, the component comprising the initiator may befabricated separately from the other component(s) of the applicator tipand assembled prior to attachment to the applicator container.

The applicator tip may also be in the form of a nozzle for atomizingliquid polymerizable and/or cross-linkable materials. Conical, flatspray or condensed stream nozzles are suitable.

The applicator tip according to the present invention may be utilized invarious devices. For example, manual methods of application may includeutilization of hand-held devices such as syringes, adhesive guns,pipettes, eyedroppers and the like.

The applicator tip and the applicator container may also be an integralunit. The unit may be preformed as a single piece and charged withpolymerizable and/or cross-linkable material. After application ofmaterial from the applicator container, the unit may be discarded.Additionally, such an integral applicator tip/applicator container unitmay be fashioned to provide the capability of recharging the unit withnew material as a multiple use device.

The applicator tip may be composed of any of a variety of materialsincluding polymerized materials such as plastics, foams, rubber,thermosets, films or membranes. Additionally, the applicator tip may becomposed of materials such as metal, glass, paper, ceramics, cardboardand the like. The applicator tip material may be porous, absorbent oradsorbent in nature to enhance and facilitate loading of the initiatoron or within the applicator tip. For example, the applicator tip may becomposed of a material having random pores, a honey-comb material, amaterial having a woven pattern, etc. The degree of porosity will dependon the materials being used.

The applicator tip according to the present invention, where it connectsto the applicator container, may have an elongated tubular portion, outof which the mixed polymerizing and/or cross-linking material isexpelled. A portion of the applicator tip which is immediatelydownstream of the applicator container is advantageously porous in orderto avoid a sharp pressure drop and ensure a constant mixed ratioprofile. The structure can preferably trap any barriers or materialsused to separate multiple components within the applicator container.Thus, any such barriers will not clog the device.

Initiators that initiate polymerization and/or cross-linking of thematerial may be applied to a surface portion or to the entire surface ofthe applicator tip, including the interior and the exterior of the tip.Alternatively, the initiator may be coated only on an internal surfaceof the applicator tip. Preferably, only a portion of the interior of theapplicator tip is coated with the initiator.

The initiator on the applicator tip may be in the form of a solid, suchas a powder or a solid film, or in the form of a liquid; such as aviscous or paste-like material. The initiator may also include a varietyof additives, such as surfactants or emulsifiers. Preferably, theinitiator is soluble in the polymerizable and/or cross-linkablematerial, and/or comprises or is accompanied by at least one surfactantwhich, in embodiments, helps the initiator co-elute with thepolymerizable and/or cross-linkable material. In embodiments, thesurfactant may help solubilize the initiator in the polymerizable and/orcross-linkable material.

Particular initiators for particular systems may be readily selected byone of ordinary skill in the art without undue experimentation. Suitableinitiators include, but are not limited to, detergent compositions;surfactants: e.g., nonionic surfactants such as polysorbate 20 (e.g.,Tween 20™), polysorbate 80 (e.g., Tween 80™) and poloxamers, cationicsurfactants such as benzalkonium chloride and tetrabutylammoniumbromide, anionic surfactants such as sodium tetradecyl sulfate, andamphoteric or zwitterionic surfactants such asdodecyldimethyl(3-sulfopropyl)ammonium hydroxide, inner salt; amines,imines and amides, such as imidazole, tryptamine, urea, arginine andpovidine; phosphines, phosphites and phosphonium salts, such astriphenylphosphine and triethyl phosphite; alcohols such as ethyleneglycol, methyl gallate, ascorbic acid, tannins and tannic acid;inorganic bases and salts, such as sodium bisulfite, magnesiumhydroxide, calcium sulfate and sodium silicate; sulfur compounds such asthiourea and polysulfides; polymeric cyclic ethers such as monensin,nonactin, crown ethers, calixarenes and polymeric epoxides; cyclic andacyclic carbonates, such as diethyl carbonate; phase transfer catalystssuch as Aliquat 336; organometallics such as cobalt naphthenate andmanganese acetylacetonate; and radical initiators and radicals, such asdi-t-butyl peroxide and azobisisobutyronitrile. The polymerizable and/orcross-linkable material may also contain an initiator which is inactiveuntil activated by a catalyst or accelerator (included within the scopeof the term “initiator” as used herein) in the applicator tip.Initiators activated by stimulation such as heat and/or light (e.g.,ultraviolet or visible light) are also suitable if the tip and/orapplicator is appropriately subjected to such stimulation.

The initiator may be applied to the surface of the applicator tip or maybe impregnated or incorporated into the matrix or internal portions ofthe applicator tip. For example, the initiator may be applied to theapplicator tip by spraying, dipping, or brushing the applicator tip witha liquid medium containing the initiator. The liquid medium may includenon-aqueous solvents, such as ether, acetone, ethanol, pentane ormixtures thereof; or may include aqueous solutions. Preferably, theliquid medium is a low boiling point solvent.

Suitable applicators for application of the adhesive of the presentinvention include those described in copending application Ser. No.08/488,411, the subject matter of which is incorporated herein byreference. A preferable applicator is a crushable swab applicator.

Specific methods which may use an adhesive composition of the presentinvention include methods for repairing damaged living tissue to preventthe escape of fluids therethrough by holding damaged tissue edgestogether in an abutting relationship, applying to the abutting tissuethe monomer composition of the present invention, and allowing thecomposition to polymerize; methods for stemming the flow of blood fromvessels which comprises holding damaged regions of the blood vesselstogether, applying the present monomer composition to the damagedregions and allowing the composition to polymerize; and methods ofbonding bone tissue to promote healing of weak or fractured bones whichcomprises holding damaged bone tissue together, applying to the damagedtissue the present monomer composition, and allowing the composition topolymerize.

Repairing injured tissues (for example, to control bleeding) comprises,in general, sponging to remove superficial body fluids, holding injuredtissue surfaces together in an abutting relationship and subsequentapplication to the exposed abutted tissue of the present adhesivecomposition. The composition polymerizes to a thin film of polymer whilein contact with the abutted tissue surface. Tissues which are notbleeding or otherwise covered by body fluids need not be sponged first.More than one coating or application of monomer composition may beapplied to the abutted tissue surface.

The monomers are readily polymerized to addition-type polymers andcopolymers, which are generally optically clear (as films).

In most bonding applications using the compositions of this invention,polymerization of the monomers is catalyzed by small amounts of moistureon the surface of the adherents; thus desired bonding of tissues orhemostasis proceeds well in the presence of blood and other body fluids.The bonds formed are of adequate flexibility and strength to withstandnormal movement of tissue. In addition, bond strength is maintained asnatural wound healing proceeds.

Compositions employed in the invention are preferably sterilizable byconventional methods that include, but are not limited to, autoclave oraseptic filtration techniques.

EXAMPLES I-VI

The compositions according to the present invention are preparedutilizing conventional mixing equipment. For example, the process may beconducted as follows:

To a surgical grade cyanoacrylate in a round-bottom flask is added theplasticizer, the acidic stabilizer, and other formulation components asdescribed herein. The resulting mixture is mechanically stirred until itis homogeneous.

The invention is further illustrated by the following non-limitingexamples.

In the following examples, various amounts of plasticizer (i.e., acetyltributyl citrate) are utilized in adhesive compositions of the presentinvention that illustrate the effects on the strengths of the bondsformed by the adhesive.

The data presented in Table I is generated using the following method:

1. A 2″ incision is made in a 5 ½″×5 ½″ sheet of latex ({fraction(1/16)}″ thickness).

2. An adhesive composition (i.e., 2-octyl cyanoacrylate) is appliedtopically to the incision with a crushable swab with a polymerizationinitiated tip. The interface of the incision must not be inadvertentlyglued.

3. After curing for one hour, the sheet is fixed between two sheets ofplexiglass. The bottom sheet is equipped with a pressure transducer andgas inlet. The upper sheet has a 3 ⅝″ hole centrally located in it. Thetest piece is positioned such that the glued side is facing the uppersheet of plexiglass containing the 3 ⅝″ hole.

4. The valve controlling gas flow is opened to pressurize the testmaterial. Pressure is increased until failure.

5. Peak pressure is recorded by the transducer and :recorded on a chartrecorder. Ten determinations per test material are made.

The results are as follows:

TABLE I Concentration (w/w%) BURST EXAMPLE of Plasticizer PRESSURE (psi)I 0.0 3.9 II 5.7 3.9 III 9.1 3.7 IV 15.2 3.2 V 20.0 2.6 VI 25.9 2.1

EXAMPLES VII-X

In order to demonstrate the unexpected superiority of the in vivo filmstrength provided by the adhesive composition and application methodaccording to the present invention, various methods and materials forwound closure and topical administration of various surgical woundclosure devices are evaluated (Examples VII-X). In vivo strength isobjectively defined by the amount of ultimate pressure required toinduce wound failure (i.e., the amounts of vacuum pressure required toopen the wound). The biomechanical analysis is performed using theDimensional Analysis Systems (DAS), (DIMENSIONAL ANALYSIS SYSTEMS,LEONIA, N.J.). This technology is specifically designed for objective invivo biomechanical characterization of linear incision wounds. Incontrast to previous biomechanical analysis methods (e.g., uniaxialtensiometers), the DAS applies a multi-axial stress to a wound which ismore analogous to stresses experienced in clinical conditions. Moreover,the DAS does not require tissue manipulation or destructive incision ofspecimens prior to testing. Therefore, sensitive, reliable andreproducible measurements of fragile wounds may be obtained in the earlyphases of healing. The DAS further eliminates the artifact error and theexperimental variables introduced by excisional methods such as,non-viable tissue samples, inconsistent variation of sample dimensions,and flawed edges from excising tissues.

The male Sprague Dawley rat is selected for the animal model because ofits genetic homogeneity, ease of handling and housing, and overallpopularity as a linear incision wound model, thus allowing comparison ofdata to other similar studies. This model has been used extensively inincisional wound research, which is well documented in the literature.

Male Sprague Dawley rats, purchased from Harlan Sprague Dawley, Inc.(Indianapolis, Ind.) are utilized in the tests. All animals are heldseven days prior to the procedures for stabilization of diet andbehavior. Four groups of rats (Groups A-D), each with a different woundclosure method and/or surgical adhesive, are tested under identicalconditions. Each of the specimens are tested for film strength one hourafter closure of the linear incision wounds.

EXAMPLE VII

In the first group of rats, designated as Group A, a one-stroketechnique for application of tissue adhesive is employed. An adhesive ofthe present invention containing about 6% by weight of plasticizer withacetic acid as an acidic stabilizer (pK_(a)=4.8) in 2-octylalpha-cyanoacrylate is applied with a compressible ampule with a swabtip (crushable swab applicator) and is passed along the opposing woundedges in a “one-stroke” fashion for topical administration.

EXAMPLE VIII

In the second group of rats, designated as Group B, linear incisions areclosed with the same adhesive using a multi-stroke technique. Theadhesive is applied with a compressible ampule passed more than oncealong the opposing wound edges in a “multi-stroke” fashion, resulting in2-3 distinct applications of adhesive.

EXAMPLE IX

In the third group of rats, designated as Group C, linear incisionwounds are closed with the same adhesive using a minimal surfaceexposure technique. Adhesive is applied with a UniJect™ syringe(available from Horizon, Santa Ana, Calif., USA) with approximately 3-4drops in an attempt to limit the amount of adhesive exposed to the skinsurface, thus administering the adhesive to the opposing wound edgesonly.

EXAMPLE X

In the fourth group of rats, designed as Group D, linear incision woundsare closed with Histoacryl™ (a surgical adhesive available from B. BraunMelsungen AG of Germany) using the application technique of Example IX.

The results from the in vivo biomechanical analyses are displayed inTable II below. As illustrated in Table II, there are significantdifferences observed between all groups at the one hour time periodstudied. Group B, the multi-stroke technique, demonstrates a significantincrease in ultimate pressure in comparison to Groups A & C. This datasuggests that increasing the amount of adhesive applied may allow forhigher in vivo strength. Group D reveals a highly significant decreasein in vivo strength in comparison to all groups evaluated.

TABLE II Reveals statistical results for direct comparisons of thealternate methods and other techniques at 1 hour post-application.Number of In Vivo strength Group Incisions (mmHg) A:one stroke 10 110.30B:multi-stroke 10 214.57 C:minimal 10 94.36 surface exposureD:Histoacryl 10 62.80 (minimal surface exposure)

EXAMPLE XI

The efficacy of the same tissue adhesive according to the presentinvention is tested in its ability to close skin incisions in a pigmodel. The tissue adhesive, Histoacryl™, is used as a control.

Incisions are made on each side of the back of these pigs with sterilescalpel blades at a controlled depth for the incisions. The incisionsare closed either with the test material or with the control. The sameadhesive of the present invention, incorporated into an applicator, wasapplied onto the opposed abutted edges of the wound until the adhesivepolymerizes (i.e., the adhesive is no longer sticky to the touch). Theapplicator is a transparent, flexible, plastic cylinder with anabsorbent head (crushable swab). Within the cylinder is a glass vialcontaining the adhesive which is broken by squeezing the cylinder. Asthe applicator is inverted, the adhesive is squeezed out of the cylinderinto the head and then onto the skin. Histoacryl® is also applied withan applicator, which is a sealed plastic ampule with a narrow neck. Theampule is attached to a 27 gauge hypodermic needle. The ampule isinverted and the adhesive is applied by squeezing the ampule anddripping microdrops from the end of the needle onto the opposed edges ofthe incision. Care is taken not to touch the skin with the needle tip.The method of applying Histoacryl® has been described by J. Quinn and J.Kissick (1994, “Tissue adhesives for laceration repair during sportingevents”, Clin. J. Sport Med., 4:245-248).

Observations are made frequently during the recovery phase, recordedapproximately four hours postoperatively, and then daily to determine ifany of the incisions partially or completely separates (dehiscence), andif there are any adverse tissue responses. If a wound opens during theobservation period, it is not reclosed.

TABLE III DEHISCENCE OF PIG SKIN INCISIONS Invention ™ Histoacryl ™ PIG1 Number of incisions 4 4 Number of partial or 0 1 complete dehiscencesPIG 2 Number of incisions 4 4 Number of partial or 0 4 completedehiscences PIG 3 Number of incisions 4 4 Number of partial or 0 2complete dehiscences

The pigs are observed for wound dehiscence for 10 days. Dehiscence isnot observed in any incision closed with the adhesive of the invention.Partial or complete dehiscence is observed in 7 of the 12 incisionsclosed with Histoacryl™. Complications such as infection or necrosis arenot observed.

What is claimed is:
 1. A method of joining together living tissuesurfaces of an incision or a laceration, comprising: (a) holdingtogether at least two tissue surfaces of an incision or laceration toform abutted tissue surfaces; (b) applying across said abutted tissuesurfaces an amount of a sterile adhesive composition comprising at leastone α-cyanoacrylate monomer, which forms a medically acceptable polymer;and (c) maintaining said tissue surfaces in contact until saidcomposition polymerizes to form a film of polymerized composition onsaid abutted tissue surface, said film having a thickness of at least0.1 mm and said film having a higher film strength than a film of lesserthickness.
 2. A method of joining together living tissue surfaces of anincision or laceration, comprising: (a) holding together at least twotissue surfaces of an incision or laceration to form abutted tissuesurfaces; (b) applying across said abutted tissue surfaces an amount ofa sterile adhesive composition comprising at least one α-cyanoacrylatemonomer, which forms a medically acceptable polymer; and (c) maintainingsaid tissue surfaces in contact until said composition polymerizes toform a film of polymerized composition on said abutted tissue surface,said film having a thickness of at least 0.1 mm and said film having ahigher film strength than a film of lesser thickness, wherein saidcomposition further comprises at least one plasticizing agent in anamount ranging from 3 wt. % to 9 wt. % of said composition and at leastone acidic stabilizing agent having a pK_(a) of from about 1 to about 5.3. A method according to claim 1, wherein more than one application ofsaid adhesive composition is provided across said abutted tissuesurfaces.
 4. A method according to claim 3, wherein said adhesivecomposition applied across said abutted tissue surfaces is allowed to atleast partially polymerize prior to subsequent coatings or applicationsof said adhesive composition.
 5. A method according to claim 3, whereinan adhesive composition having a monomer different from the monomer of aprevious coating is applied as a subsequent coating.
 6. A methodaccording to claim 1, wherein said adhesive composition polymerizes toform a bridge across said abutted tissue surfaces.
 7. A method accordingto claim 1, wherein said film has a thickness of 0.2 mm to 3.0 mm.
 8. Amethod according to claim 1, wherein said adhesive composition isapplied using a crushable swab applicator.
 9. The method of claim 1,wherein said adhesive composition comprises at least one plasticizingagent present in the composition in an amount of from 0.5 wt. % to 16wt. % of the composition; and at least one acidic stabilizing agenthaving a pK_(a) ionization constant of from about 0 to about
 7. 10. Afilm formed across abutted tissue surfaces made by the method of claim2.
 11. A method of forming a biocompatible film across abutted tissuesurfaces of an incision or laceration, comprising (a) holding togetherat least two tissue surfaces of an incision or laceration to formabutted tissue surfaces, (b) applying across said abutted tissuesurfaces a sterile adhesive biocompatible monomer composition comprisingat least one α-cyanoacrylate monomer, and (c) allowing components ofsaid composition to polymerize and form a biocompatible film on saidabutted tissue surfaces having a film strength of at least 70 mmHg ofpressure required to induce wound failure and said film having athickness of at least 0.1 mm.
 12. A method according to claim 11,wherein said film strength is at least 90 mmHg of pressure required toinduce wound failure.
 13. A method according to claim 11, wherein saidfilm strength is at least 100 mmHg of pressure required to induce woundfailure.
 14. The method according to claim 2, wherein said at least oneplasticizing agent is present in an amount of from 4 wt. % to 7 wt. % ofthe composition.
 15. The method of claim 11, wherein saidα-cyanoacrylate is selected from the group consisting of 2-octylcyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butylcyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate,2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl cyanoacrylate, and1-methoxy-2-propyl cyanoacrylate.
 16. The method of claim 1, whereinsaid α-cyanoacrylate is selected from the group consisting of 2-octylcyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butylcyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate,2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl cyanoacrylate, and1-methoxy-2-propyl cyanoacrylate.
 17. A method of joining togetherliving tissue surfaces of an incision or a laceration, comprising:holding together, without adhesives, at least two tissue surfaces of anincision or a laceration to form abutted tissue surfaces; applyingacross said abutted tissue surfaces a film of a sterile adhesivecomposition comprising at least one α-cyanoacrylate monomer; andallowing said composition to polymerize in a film at least 0.1 mm thick,said film having a higher strength than a film of lesser thickness. 18.A method of joining together living tissue surfaces of an incision or alaceration, comprising: (a) holding together at least two tissuesurfaces of an incision or a laceration to form abutted tissue surfaces;(b) applying across said abutted tissue surfaces a sterile adhesivecomposition comprising at least one α-cyanoacrylate monomer, to form afilm of a medically acceptable polymer; (c) applying at least onesubsequent coating of the adhesive composition on top of said film; and(d) maintaining said tissue surfaces in contact until said compositionpolymerizes to form a film of polymerized composition on said abuttedtissue surfaces, said film being at least 0.1 mm thick and said filmhaving a higher strength than a film of lesser thickness.
 19. The methodof claim 11, consisting essentially of steps (a)-(c).
 20. A methodaccording to claim 11, wherein said film has a thickness of at least 0.2mm.
 21. A method according to claim 1, wherein said film has a thicknessof at least 0.2 mm.
 22. A method according to claim 2, wherein said filmhas a thickness of at least 0.2 mm.
 23. A method according to claim 17,wherein said film has a thickness of at least 0.2 mm.
 24. A methodaccording to claim 18, wherein said film has a thickness of at least 0.2mm.